Bartlett, John A MD*; Johnson, Judy MS, MBA†; Herrera, Gisela MD‡; Sosa, Nestor MD§; Rodriguez, Alan MD‖; Liao, Qiming PhD†; Griffith, Sandy PharmD†; Irlbeck, David MS†; Shaefer, Mark S PharmD†; for the Clinically Significant Long-Term Antiretroviral Sequential Sequencing Study (CLASS) Team
The current standard of care for the initial treatment of HIV-1 infection involves the use of combination antiretroviral therapy (ART) to inhibit reverse transcriptase and protease activity, or reverse transcriptase activity alone.1,2 In clinical trials analyzed with the intent-to-treat (ITT) principle, 28% to 78% of subjects receiving these combinations have suppression of plasma HIV-1 RNA levels to <50 copies/mL at week 96.3-5 Conversely, the remaining subjects not reaching this threshold are at higher risk for virologic failure on treatment and the important consequence of drug-resistant viruses. When resistance to first-line drugs develops, the therapeutic options for secondary therapy may be limited because of cross-resistance with other agents in each antiretroviral class. If a class-sparing therapeutic strategy targets 1 or 2 drug classes and failure develops with resistance, introduction of drugs from different treatment classes may still result in long-term suppression of HIV-1 replication. The development of potent regimens that suppress viral replication with limited use of treatment classes allows this strategy to be evaluated prospectively. In addition, concern about the long-term tolerability of each class of antiretroviral drug may affect patient acceptance and safety, and therefore have an impact on virologic outcome. The optimal sequential use of these therapies with class-sparing approaches could thus result in more durable viral suppression and better tolerability for patients.
ESS40001 Clinically Significant Long-term Antiretroviral Sequential Sequencing Study (CLASS) was an open-label, multicenter, randomized trial to study initial treatment regimens of 300 mg of abacavir (ABC) plus 150 mg of lamivudine (3TC) given twice daily with a nonnucleoside reverse transcriptase inhibitor (NNRTI; 600 mg of efavirenz [EFV] once daily), an enhanced protease inhibitor (PI; 1200 mg of amprenavir [APV]/200 mg of ritonavir [RTV] once daily), or a third nucleoside reverse transcriptase inhibitor (NRTI; 30 or 40 mg of stavudine [d4T] twice daily, with the dose being weight-dependent). The daily pill counts were 7 for the NNRTI arm, 14 for the PI arm, and 6 for the NRTI arm. Subjects in the PI arm were switched from APV/RTV to 1400 mg of fosamprenavir (FPV)/200 mg of RTV once daily during the study as FPV became available (mean duration of APV/RTV was 188 days). The daily pill count for the PI arm decreased from 14 to 8 after subjects were switched from APV/RTV to FPV/RTV, and the last 13 subjects enrolled into the PI arm started FPV/RTV from baseline (BL).
Eligible subjects were HIV-infected therapy-naive (<2 weeks of prior ART) persons with BL HIV-1 RNA levels ≥5000 copies/mL and CD4 counts ≥50 cells/mm3. Subjects were excluded if they had any of the following laboratory abnormalities: hemoglobin <9.1 g/dL for men and <8.9 g/dL for women, absolute neutrophil count <1000/mm3, platelet count <100,000/mm3, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 times the upper limits of normal, total bilirubin or serum amylase >1.5 times the upper limit of normal, or serum creatinine >1.5 times the upper limit of normal. Subjects were also excluded if they had a history of a US Centers for Disease Control and Prevention (CDC)-defined clinical category C event within 45 days of screening (with the exception of cutaneous Kaposi sarcoma); if they were enrolled in 1 or more investigational drug studies that might have an impact on HIV RNA suppression; if they were pregnant or breast-feeding; if they had a history of allergy to any of the study medications or their excipients; if they had a serious medical condition, such as diabetes, congestive heart failure, cardiomyopathy, or other cardiac dysfunction; if they had a history of bilateral peripheral neuropathy of grade 2 or greater; if they had a history of clinically relevant pancreatitis or hepatitis within 6 months of screening; if they had malabsorption syndrome or another gastrointestinal dysfunction that might interfere with drug absorption or render the subject unable to take oral medication; if they were taking any of the following medications within 21 days before starting the study drug or anticipated need during the study: astemizole, bepridil, cisapride, dihydroergotamine, ergotamine, midazolam, terfenadine, triazolam, rifampin, rifabutin, phenobarbital, phenytoin, carbamazepine, erythromycin, clarithromycin, ketoconazole, itraconazole, cimetidine, amiodarone, or hypericum; if they required treatment with immunomodulating agents, such as systemic corticosteroids, interleukins, vaccines, or interferons, within 4 weeks before study entry or if they had received an HIV immunotherapeutic vaccine within 3 months before entry; if they required radiation therapy or cytotoxic chemotherapeutic agents within 4 weeks before entry or had an anticipated need for these agents within the study period; or if the subject, in the opinion of the site investigator, was unlikely to complete the 96-week dosing period and protocol evaluations or had a preexisting mental, physical, or substance abuse disorder that might interfere with the subject's ability to complete the study.
Subjects were stratified at entry according to screening plasma HIV RNA levels (<100,000 copies/mL and ≥100,000 copies/mL). The study was approved by the responsible institutional review boards and/or ethics committee at each site, and all subjects provided informed consent. All laboratory assessments were performed at each scheduled visit, including screening, BL, every 4 weeks until week 24, and every 8 weeks until study completion at 96 weeks.
Subjects experiencing a treatment-limiting adverse event attributable to a study drug were allowed to substitute another drug in the same class after discussion with GlaxoSmithKline. For example, d4T was substituted for ABC in the event of a hypersensitivity reaction, with the exception of the NRTI arm, where didanosine (ddI) was substituted. The subjects with in-class substitutions were analyzed as remaining on their first treatment. A second regimen of ART was predefined for cases of toxicity requiring the use of new drug classes or when virologic failure occurred. A subject was also switched in the event of treatment-limiting toxicity that, in the opinion of the investigator, required discontinuation of the treatment regimen. Subjects could switch from primary or secondary therapy to best therapy (chosen at the discretion of the investigator) because of intolerance or virologic failure. Adverse events were graded with the Division of AIDS grading system. Virologic failure was defined as (1) before week 24, reduction of plasma HIV-1 RNA level to <400 copies/mL with a subsequent increase to ≥1265 copies/mL at 2 consecutive study visits; (2) at week 24, plasma HIV-1 RNA level ≥400 copies/mL with evidence of incomplete suppression of viral replication at prior study visits; and (3) after week 24, plasma HIV-1 RNA level ≥1265 copies/mL on 2 consecutive measurements 2 to 4 weeks apart. The virologic threshold of 1265 copies/mL was chosen because it represented a 0.5-log10 copies/mL increase over 400 copies/mL, and therefore accounted for assay variability. Any subject who never achieved a virologic response and discontinued before the 24-week visit was also considered to have virologic failure.
Resistance was assessed by the HIV-1 TruGene Genotype Assay (Bayer Diagnostics [formerly Visible Genetics, Inc.], Suwanee, GA). Resistance mutations detected at virologic failure were compared with those observed from a BL genotype. The BL resistance results were not available for investigators to guide the regimen choice. Because the study and analysis were completed in 2003, the 2003 International AIDS Society (IAS)-USA consensus guidelines were used to define mutations associated with resistance, although the most recent IAS-USA guidelines (November 2005) were also used in an unplanned analysis.
After the screening visit, eligible subjects were randomized (1:1:1 ratio) into 1 of 3 treatment arms. Central randomization with a block size of 6 was used, and the randomization was stratified by screening HIV-1 RNA levels (<100,000 copies/mL or ≥100,000 copies/mL). The ITT population included all subjects who were randomized and completed the BL visit, regardless of a change in therapy because of an in-class substitution or switching to secondary or best (chosen at the discretion of the investigator) therapy. The safety population included all subjects in the ITT population who received at least 1 dose of the initial regimen. In the ITT/Missing = Failure (M = F) analyses, all subjects in the ITT population were included, and missing data were counted as failures. In the ITT/observed analyses, subjects with available data were analyzed and missing data, regardless of the reason, were ignored.
The primary end points of the CLASS study were the proportion of subjects with HIV-1 RNA levels <400 copies/mL at week 96 and the time to treatment failure, defined as treatment-limiting toxicity or virologic failure. Other secondary end points included the proportion of subjects with HIV-1 RNA levels <50 copies/mL, change from BL in CD4 cell count, time to virologic failure, duration of virologic suppression, genotypic resistance, and safety. Overall comparisons among the 3 treatment arms in the proportion of subjects with HIV-1 RNA levels <400 copies/mL and <50 copies/mL were made using the Cochran Mantel-Haenszel tests, controlling for strata differences. The log-rank test was used for comparison of time to treatment failure, time to virologic failure, and duration of virologic suppression. The Kruskal-Wallis test was used to compare change from BL in CD4 cell count. There were 3 pairwise comparisons between the treatment arms (NNRTI vs. PI, NNRTI vs. NRTI, and PI vs. NRTI), and the Bonferroni correction (α = 0.017) was used for these pairwise comparisons.
The resistance cost (Cp) of a treatment regimen was defined as the difference in future drug options (FDO) between BL and time of virologic failure.6 The 2003 Stanford inferred Cp score was used to calculate the binary sensitivity scores for each drug, and a cutoff point of 15 was chosen to distinguish between susceptible and resistant. Because of the limitations of missing data and the relatively small sample size, summary statistics of FDO and Cp by treatment arm were analyzed descriptively and with a comparison of Cp using the Kruskal-Wallis test.
All statistical tests were 2-sided and performed with a 0.05 type I error rate (except pairwise comparisons). All data manipulation, tabulations, and calculations were performed using SAS (version 6.12; SAS Institute, Cary, NC) on a system of UNIX computers.
Study enrollment occurred between April 2000 and January 2001. Two hundred ninety-one subjects constituted the ITT population (randomized and completed their BL visit). BL demographics and clinical characteristics are summarized in Table 1. Study subjects were mostly nonwhite (72%), had a mean BL HIV-1 RNA level of 4.85 log10 copies/mL with 42% >100,000 copies/mL, and had a mean BL CD4 count of 303 cells/mm3 with 35% <200 cells/mm3. Demographic and clinical characteristics were balanced across the 3 study arms.
Subject disposition is summarized in Figure 1. Premature discontinuation was defined as any discontinuation before completing the scheduled 96 weeks. Sixty-two subjects (21%) discontinued study medication prematurely. There were no statistically significant differences between the 3 treatment arms in the time to study discontinuation, although there was a trend toward later discontinuation in the NRTI arm (P = 0.088). Twenty-nine subjects (10%) were lost to follow-up over 96 weeks.
The subjects experiencing virologic- and toxicity-related failures who switched to a second regimen treatment or best therapy or who prematurely discontinued are listed in Figure 1 by treatment arm. There were 21 premature discontinuations in the NNRTI and PI arms on first treatment regimens compared with 11 in the NRTI arm. For the PI arm, 11 subjects prematurely discontinued the study while taking APV/RTV and 10 subjects prematurely discontinued while taking FPV/RTV.
Overall, 32 failures occurred on the first treatment regimen, resulting in treatment switches (16 virologic and 16 toxicity related): 28 subjects switched to a second protocol-defined regimen, and 4 switched directly to best therapy. Only 3 first-regimen failures occurred in the NNRTI arm (all toxicity related) compared with 16 in the NRTI arm (9 virologic and 7 toxicity related) and 13 in the PI arm (7 virologic and 6 toxicity related). Relatively few subjects experienced virologic failure (n = 1), toxicity-related failure (n = 1), or premature discontinuation (n = 9) on second-line or best therapy. Time to treatment failure, time to first virologic failure, and time to second virologic failure were not significantly different across the 3 arms (Fig. 2). The overall duration of viral suppression (<400 copies/mL) was significantly longer for the NNRTI arm (P = 0.017), however. Pairwise comparisons showed a statistically significant difference in favor of the NNRTI arm compared with the NRTI arm, but there was no significant difference in duration of viral suppression between the NNRTI and PI arms or NRTI and PI arms. Ten subjects (5 in the NNRTI arm, 2 in the PI arm, and 3 in the NRTI arm) had clinical disease progression. Seven of the 10 subjects had clinical disease progression from CDC class A to CDC class B, and only 3 subjects had clinical disease progression to CDC class C. There were 3 deaths (1% of the overall population). One subject in the NNRTI arm died from lymphoma 1 month after starting on study treatment, and 2 subjects died in the PI arm (1 with necrotizing pneumonia after 15 months on study treatment and 1 with anasarca and renal failure after 10 months on study treatment). There were no differences in clinical disease progression or number of deaths by study arm, and none of the deaths were judged to be related to study medications.
After 96 weeks, 74% of subjects in the NNRTI arm, 66% of subjects in the PI arm, and 79% of subjects in the NRTI arm had plasma HIV-1 RNA levels <400 copies/mL (ITT/M = F); 96% (NNRTI arm), 89% (PI arm), and 92% (NRTI arm) achieved <400 copies/mL in ITT/observed analyses. There were no significant differences between study arms in the percentages <400 copies/mL in the ITT/M = F or ITT/observed analyses (Figs. 3A, B). After 96 weeks, 68%, 58%, and 61% for NNRTI arm, PI arm, and NRTI arm, respectively, had plasma HIV-1 RNA levels <50 copies/mL (ITT/M = F), and 88% (NNRTI), 79% (PI), and 71% (NRTI) achieved <50 copies/mL (ITT/observed) (see Figs. 3C, D). At week 96, there were no significant differences between study arms in the percentages with plasma HIV-1 RNA levels <50 copies/mL. The proportion of study subjects from the NNRTI arm with plasma HIV-1 RNA levels <50 copies/mL was consistently higher than the proportion in the PI or NRTI arm, however, and was significantly higher at earlier time points (ITT/M = F; P = 0.018 at week 24 and P = 0.047 at week 48). The mean changes in plasma HIV-1 RNA level from BL to week 96 were −3.13, −2.91, and −2.92 log10 copies/mL for NNRTI arm, PI arm, and NRTI arm, respectively, and were not significantly different across the 3 arms. In the stratum of subjects with BL plasma HIV-1 RNA levels >100,000 copies/mL at 96 weeks, 77% (NNRTI arm), 72% (PI arm), and 73% (NRTI arm) had levels <400 copies/mL (ITT/M = F) and 65% (NNRTI arm), 64% (PI arm), and 49% (NRTI arm) had levels <50 copies/mL. These percentages were not significantly different.
CD4+ cell counts increased progressively during the study, with mean changes from BL of 194, 167, and 193 cells/mm3 at 48 weeks and 267, 256, and 258 cells/mm3 at 96 weeks for the NNRTI arm, PI arm, and NRTI arm, respectively (ITT/observed). There were no significant differences in the mean changes from BL between the 3 arms at week 48 or week 96.
There were 2 subjects randomized to the PI arm who never took a dose of study drugs and discontinued from the study after BL; these 2 subjects were excluded from analyses of the safety population. The incidences of grade 2 through 4 drug-related adverse events were similar across arms (Table 2). Adverse events leading to study discontinuation were infrequent, and comparable rates were observed across the 3 arms. Serious adverse events were also similar across the arms, and most represented ABC hypersensitivity reactions (overall incidence of 7.3%). All ABC hypersensitivity reactions were of grade 2 or 3 severity, with the exception of single grade 1 (PI arm) and grade 4 (NRTI arm) reports.
Sleep disorders and altered dreams were observed more frequently in the NNRTI arm, diarrhea more commonly in the PI arm, and elevated lactate and peripheral neuropathy more commonly in the NRTI arm. There were 6 reports of drug-related peripheral neuropathy and 5 reports of lactic acidosis in the NRTI arm. All subjects except 1 were on the original randomized ABC/3TC/d4T regimen when these adverse events occurred, and 1 subject had peripheral neuropathy while on 3TC/d4T/ddI.
Lipid elevations were observed across all 3 arms, although grade 3 or greater triglyceride elevations were observed more frequently in the PI arm (15 vs. 7 for the NNRTI arm and 9 for the NRTI arm). Grade 3 or greater AST elevations were observed in 7 subjects from the NNRTI arm, 6 subjects from the PI arm, and 4 subjects from the NRTI arm.
Drugs and Drug Classes Used
Substitutions were allowed within a drug class for subjects who experienced drug-related toxicities. In the NRTI arm, 13 substitutions occurred; 11 subjects substituted zidovudine for d4T, and 2 subjects substituted ddI for ABC. In the NNRTI arm, 13 substitutions occurred in 11 subjects; 7 subjects substituted d4T for ABC, 3 subjects substituted nevirapine for EFV, and 1 subject substituted ddI for ABC. In the PI arm, 6 substitutions occurred (d4T for ABC in all cases).
Subjects in the NNRTI arm were less likely to use drugs other than the originally assigned regimen (14%) compared with the NRTI arm (31%) and the PI arm (27%). There were fewer subjects in the NNRTI arm who had used all 3 drug classes (NNRTI [n = 2] vs. PI [n = 14] vs. NRTI [n = 15]). Eighty-two percent of subjects in the NRTI arm received only 1 drug class during the study. Importantly, there were inherent imbalances between the 3 arms in the number of drugs and classes used (minimum of 3 drugs and 1 class in the NRTI arm, minimum of 3 drugs and 2 classes in the NNRTI arm, and minimum of 4 drugs and 2 classes in the PI arm).
Sixty-three subjects experienced protocol-defined virologic failure on their first regimen (15 in the NNRTI arm, 24 in the PI arm, and 24 in the NRTI arm). Genotypes were obtained at BL and discontinuation for 41 of 63 subjects (6 in the NNRTI arm, 18 in the PI arm, and 17 in the NRTI arm). Of the 22 virologic failures with missing genotype data, 2 in the NRTI arm were genotype failures at the time of failure, 7 had no BL specimens available (2 in the NNRTI arm, 3 in the PI arm, and 2 in the NRTI arm), and 13 did not have samples available at the time of failure (7 in the NNRTI arm, 3 in the PI arm, and 3 in the NRTI arm). Of the 13 subjects with no specimen available at the time of failure, all but 3 withdrew at BL or within 2 weeks after BL.
Of the 41 subjects with genotypes at BL and virologic failure, 20 had no treatment-emergent mutations. Seven subjects had BL resistance mutations: 1 with K103N in the NNRTI arm, 3 in the PI arm (1 with M41L; 1 with K219Q; and 1 with M41L, L210W, T215Y, M184V, and T69D), and 3 in the NRTI arm (2 with M41L and 1 with M184V). Twenty-one subjects had NRTI or NNRTI treatment-emergent mutations (5 of 6 from the NNRTI arm, 6 of 18 from the PI arm, and 10 of 17 from the NRTI arm; Table 3). The results were similar using the November 2005 IAS-USA guidelines, and only 1 subject in the PI arm who developed a V118I mutation was not included (not a primary mutation in the November 2005 guidelines). The most frequent treatment-emergent mutation was M184V (2, 4, and 9 subjects from the NNRTI arm, PI arm, and NRTI arm, respectively). Thymidine analogue mutations and K65R developed in 2 subjects each from the NRTI arm. L74V emerged in 1 subject in the NRTI arm and 1 subject in the PI arm. The K103N mutation emerged in 3 subjects in the NNRTI arm. The only primary PI-associated treatment-emergent mutation in the PI arm (I54I/M) emerged in 1 subject while receiving APV/RTV.
Because only 6 subjects from the NNRTI arm had genotyping results, the FDO and Cp scores were calculated only for the PI and NRTI arms. At BL, the mean FDO scores were 3.49 (N = N8) and 3.55 (N = N7) for the PI and NRTI arms, respectively. At the time of virologic failure, the mean FDO scores were 3.41 and 3.39 for the PI and NRTI arms, and the mean Cp scores were 0.085 and 0.159. There was no significant difference in Cp scores between these 2 treatment arms (P = 0.121).
CLASS was intended to guide the choice of initial ART based on long-term 96-week results. Overall, subjects did well during the trial, with 73% and 63% of subjects with HIV-1 achieving RNA levels <400 and 50 copies/mL, respectively (ITT/M = F). Ten subjects developed AIDS-defining illnesses (3%), and 3 deaths (1%) were reported during the study. CLASS is the only randomized trial to compare results between NNRTI, triple NRTI, and boosted PI regimens. There were no significant differences in the proportions of subjects with plasma HIV-1 RNA levels <400 copies/mL, the primary endpoint for this trial. The secondary analyses favored the NNRTI arm, however, with higher proportions of subjects achieving RNA levels <50 copies/mL at several time points (weeks 24 and 48), a significantly greater duration of virologic suppression, and fewer virologic failures. The lack of significant differences in the percentages of subjects with plasma HIV-1 RNA levels <50 copies/mL (ITT/M = F) at later time points may be related to several factors, including a decrease in the number of subjects with measurements at week 96 and the limited power of the CLASS study population to recognize differences. No trends in late treatment failures were identified across the 3 arms. Increases in CD4 cell counts were dramatic across all 3 study arms, with no significant differences observed between arms.
CLASS evaluated a strategic class-sparing approach to initial ART. By definition, there were differences in the number of drugs used for each study arm, depending on study arm assignment. The NNRTI arm used the fewest number of study drugs, and the PI arm was more likely to use 4 or more drugs (RTV was counted as a drug, although it was used as a boosting agent for the PI). Resistance to ART was also examined, and the defined genotyping threshold of a confirmed plasma HIV RNA level ≥1265 copies/mL provided some consistency for comparing resistance mutations across study arms. The observed resistance genotypes are consistent with those of previous reports.5,7-9 The NNRTI arm had no virologic failures and relatively infrequent resistance, and the PI arm seemed to have a lower Cp compared with the NRTI arm, although the difference was not significant in this limited number of subjects. These observations are similar to the results of other trials investigating boosted PIs and highlight a favorable attribute of boosted PI-containing regimens.9 One subject in the PI arm did develop I54I/M, in contrast to the absence of mutations from subjects in the SOLO study receiving FPV/RTV.10 Two subjects in the NRTI arm on a d4T-containing therapy developed K65R, in contrast to studies that indicate that zidovudine prevents K65R selection11,12 and consistent with another study that identified K65R mutations in d4T recipients.5 Finally, only 2 CLASS subjects on ABC and 3TC developed L74V mutations.
The virologic suppression and resistance results for these combinations should reassure clinicians, especially given recent reports of failed novel regimens. For example, 3TC plus ddI plus tenofovir regimens and 3TC plus ABC plus tenofovir regimens have each been associated with diminished virologic responses and the rapid emergence of resistance.13,14 In contrast to the low rates of virologic failure observed in CLASS subjects receiving 3TC plus ABC plus EFV, other studies of subjects receiving tenofovir plus ddI plus EFV or nevirapine15-18 have demonstrated lower proportions of subjects reaching plasma HIV RNA levels below detectable limits.
ART was tolerated well by CLASS subjects; 62 discontinued prematurely and only 8 discontinued permanently because of adverse events. Despite less optimal virologic responses, the lowest number of subjects discontinued from the NRTI arm. Twenty-eight subjects switched to a second-line drug during follow-up, but only 13 of 28 switched because of protocol-defined adverse events. The reported adverse events were consistent with the recognized toxicity profiles of the individual drugs within each arm. For example, 14% of subjects in the NNRTI arm reported vivid dreams, 14% of subjects in the PI arm reported diarrhea, and 6% of subjects in the NRTI arm developed peripheral neuropathy and 5% developed elevated lactate levels with possible related symptoms. In-class substitutions were permitted without completely switching from an originally assigned regimen, and in-class substitutions occurred most commonly because of hypersensitivity reactions. Twenty-one subjects had hypersensitivity reactions attributed to ABC (7.3%), similar to observations from previous clinical trials.7,8
CLASS used the nucleoside combination of 3TC and ABC for all 3 arms. This combination has activity and tolerability similar to those of zidovudine and 3TC.19 3TC and ABC may be given daily because of the prolonged intracellular half-life of each drug, and a coformulation of 3TC and ABC has recently received US Food and Drug Administration (FDA) approval, further decreasing the pill burden for treated patients. Results from CLASS support previous observations on the activity and tolerability of these dual nucleosides.10,20-22
CLASS is one of the first trials to use RTV-enhanced FPV dosed once daily in treatment-naive subjects. Early gastrointestinal toxicities may have led to accelerated withdrawal in this study arm. After a median of 28 weeks on study, subjects switched from 1200 mg (8 pills) of APV to FPV (2 pills) with RTV daily. This transition was associated with greater subject regimen satisfaction (data not shown), and there was little withdrawal or loss of virologic response after week 48. The low frequency of resistance mutations observed in this arm makes RTV-enhanced FPV an attractive option for initial therapy.
CLASS represents a bold attempt to define the strengths and weaknesses of alternative approaches to initial ART; however, there are limitations. The sample size population possesses adequate power to detect only large differences between study arms; therefore, type II error is possibly responsible for the failure to identify differences between arms in the primary end point measure. In an attempt to assess long-term consequences of the initial treatment assignment, CLASS applied ITT principles for analysis even when subjects had switched from a first- to second-line regimen, and this ITT methodology must be considered when reviewing study results. Finally, relatively few subjects developed resistance mutations during the study. As expected, resistance mutations in subjects from the RTV-boosted FPV and EFV arms were rare, and mutations in the d4T arm were similar to those seen historically. Resistance results from larger studies may differentiate the mutational costs associated with initial treatment regimens more clearly.
CLASS subjects demonstrated excellent clinical, virologic, and immunologic responses to initial ART strategies. Although there were no differences between arms in the primary outcome measure, the results of numerous secondary analyses favor an NNRTI-based approach. Resistance results suggest an advantage to an RTV-enhanced PI choice, balanced against increased early gastrointestinal toxicity. Taken together, these results support the currently recommended initial ART regimens.
The authors acknowledge the contributions of the 42 study sites, including their investigators and study coordinators as well as the study subjects who contributed their time and support to this project; Drs. Stephen Deeks and Neil Graham for their input into study design; Kendle International for support in study conduct; and the numerous members of the GlaxoSmithKline Study Team. Investigators involved in the study included J. Adams, G. Beal, S. Becker, N. Bellos, D. Butcher, J. Cade, P. Cook, E. DeJesus, R. Dretler, M. E. Eyster, J. Feinberg, I. Frank, S. Green, H. Grossman, F. Haas, R. Jones, H. Kessler, F. Kramer, J. Lang, C. Lucasti, S. Miles, L. Miller, M. Mogyoros, R. Myers, P. Salvato, J. Santana, K. Sathasivam, S. Schneider, S. Schrader, M. Sension, G. Sepulveda, Y. Sisay, R. Steigbigel, D. Sweet, M. Thompson, D. Ward, D. Wolde-Rufael, B. Yangco, and B. Zingman.
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